title: The 70 kDa heat shock protein protects against experimental traumatic brain injury.
abstract: Traumatic brain injury (TBI) causes disruption of the blood brain barrier (BBB) leading to hemorrhage which can complicate an already catastrophic illness. Matrix metalloproteinases (MMPs) involved in the breakdown of the extracellular matrix may lead to brain hemorrhage. We explore the contribution of the 70 kDa heat shock protein (Hsp70) to outcome and brain hemorrhage in a model of TBI. Male, wildtype (Wt), Hsp70 knockout (Ko) and transgenic (Tg) mice were subjected to TBI using controlled cortical impact (CCI). Motor function, brain hemorrhage and lesion size were assessed at 3, 7 and 14 days. Brains were evaluated for the effects of Hsp70 on MMPs. In Hsp70 Tg mice, CCI led to smaller brain lesions, decreased hemorrhage and reduced expression and activation of MMPs compared to Wt. CCI also significantly decreased right-biased swings and corner turns in the Hsp70 Tg mice. Conversely, Hsp70 Ko mice had significantly increased lesion size, worsened brain hemorrhage and increased expression and activation of MMPs with worsened behavioral outcomes compared to Wt. Hsp70 is protective in experimental TBI. To our knowledge, this is the direct demonstration of brain protection by Hsp70 in a TBI model. Our data demonstrate a new mechanism linking TBI-induced hemorrhage and neuronal injury to the suppression of MMPs by Hsp70, and support the development of Hsp70 enhancing strategies for the treatment of TBI.
authors.affiliation: Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Jong Youl
authors.initials: JY
authors.lastname: Kim
authors.forename: Nuri
authors.initials: N
authors.lastname: Kim
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zheng
authors.forename: Jong Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Midori A
authors.initials: MA
authors.lastname: Yenari
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy*; D004195:Disease Models, Animal; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use*; D020300:Intracranial Hemorrhages / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D013550:Swimming; D013997:Time Factors
chemical_list: D018840:HSP70 Heat-Shock Proteins; D018696:Neuroprotective Agents; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: Brain injury; Cerebral hemorrhage; Heat shock protein